The focus of this thesis work has been to synthesize 2, 5-diketopiperazines for testing of inhibitory properties of malarial enoyl reductase. The basis of this research was the Ugi four component synthesis reaction and it was done in conjunction with open source science. A short description of the reaction in conjunction with open source science, the benefits and drawbacks, as well as recommendations for future work is explained.
8.1 Open Source Science
By using open source science in our lab, we have proven it to be a successful tool for communicating scientific information. By posting all of our experiments on the internet (including failed reactions), we are bridging gaps between different research communities in order to solve a common problem. We were able to track the amount of internet users who visited our site each day, where they were visiting from, and what search parameters led them to our website. We benefited from the comments that users made, including one affecting the concentration of the Ugi reaction. In addition, we were able to find other scientists who were willing to collaborate with us in the molecular docking aspect as well as in vivo testing with the live parasite.
We also caught the attention of a scientist at the National Cancer Institute who is willing to screen our compounds for tumor inhibitory activities (Bradley 2007). Even though this was not the initial direction of the Ugi project, this demonstrates the potential impact open source science has on the future of research.
Researchers who participate in open source science give up their patent rights outside of the United States because the information is made public as soon as it is posted. With this it may also be difficult to publish papers in some scholarly journals because many of them establish strict criteria requiring that the information not previously been published in any form. With the increasing acceptance of pre-print servers, self-archiving and other Open Science initiatives, this situation may change in the future. (Hooker 2007)
8.2 Synthesis of 2, 5 Diketopiperazines
The Ugi reaction is a four component synthesis involving the reaction of an amine, a carboxylic acid, an aldehyde, and an isocyanide. Some of the benefits of performing this reaction include the relative ease of conducting the experiment because the reaction is carried out in a one pot fashion. In addition, the reaction works well with a variety of different components, resulting in a multitude of possible Ugi products.
In this study the Ugi product successfully formed using piperonal, 5-MFA, Boc-Gly-OH, and tert-butyl isocyanide. Phenyacetaldehyde, DOPAL, and 2-morpholinoethyl isocyanide were discovered unsuitable for the Ugi reaction because of the side reactions that dominated the reactions. The kinetics of the reaction was also studied, providing important information on the details of the reaction, such as the reversal of the imine upon addition of the Boc-Gly-OH. Scale up of the experiment is also simple and feasible because all of the reactants involved in the reaction are commercially available and inexpensive.
Although cyclization of the Ugi product to a diketopiperazine was unsuccessful, molecular modeling experiments showed that the uncyclized BOC protected and de-protected Ugi products fit into the receptor sites on the enzyme, indicating that there may be some potential biological activity associated with these compounds.
8.3 Recommendations for Future Work
Further investigation into the cyclization of the Ugi product must be performed. Isolation and characterization of the BOC de-protected intermediate could provide more information on transamidation. Compiling a library of Ugi adducts synthesized along with their kinetics information should be performed while gaining collaborators to test for any biological activities with other diseases.
The focus of this thesis work has been to synthesize 2, 5-diketopiperazines for testing of inhibitory properties of malarial enoyl reductase. The basis of this research was the Ugi four component synthesis reaction and it was done in conjunction with open source science. A short description of the reaction in conjunction with open source science, the benefits and drawbacks, as well as recommendations for future work is explained.
8.1 Open Source Science
By using open source science in our lab, we have proven it to be a successful tool for communicating scientific information. By posting all of our experiments on the internet (including failed reactions), we are bridging gaps between different research communities in order to solve a common problem. We were able to track the amount of internet users who visited our site each day, where they were visiting from, and what search parameters led them to our website. We benefited from the comments that users made, including one affecting the concentration of the Ugi reaction. In addition, we were able to find other scientists who were willing to collaborate with us in the molecular docking aspect as well as in vivo testing with the live parasite.
We also caught the attention of a scientist at the National Cancer Institute who is willing to screen our compounds for tumor inhibitory activities (Bradley 2007). Even though this was not the initial direction of the Ugi project, this demonstrates the potential impact open source science has on the future of research.
Researchers who participate in open source science give up their patent rights outside of the United States because the information is made public as soon as it is posted. With this it may also be difficult to publish papers in some scholarly journals because many of them establish strict criteria requiring that the information not previously been published in any form. With the increasing acceptance of pre-print servers, self-archiving and other Open Science initiatives, this situation may change in the future. (Hooker 2007)
8.2 Synthesis of 2, 5 Diketopiperazines
The Ugi reaction is a four component synthesis involving the reaction of an amine, a carboxylic acid, an aldehyde, and an isocyanide. Some of the benefits of performing this reaction include the relative ease of conducting the experiment because the reaction is carried out in a one pot fashion. In addition, the reaction works well with a variety of different components, resulting in a multitude of possible Ugi products.
In this study the Ugi product successfully formed using piperonal, 5-MFA, Boc-Gly-OH, and tert-butyl isocyanide. Phenyacetaldehyde, DOPAL, and 2-morpholinoethyl isocyanide were discovered unsuitable for the Ugi reaction because of the side reactions that dominated the reactions. The kinetics of the reaction was also studied, providing important information on the details of the reaction, such as the reversal of the imine upon addition of the Boc-Gly-OH. Scale up of the experiment is also simple and feasible because all of the reactants involved in the reaction are commercially available and inexpensive.
Although cyclization of the Ugi product to a diketopiperazine was unsuccessful, molecular modeling experiments showed that the uncyclized BOC protected and de-protected Ugi products fit into the receptor sites on the enzyme, indicating that there may be some potential biological activity associated with these compounds.
8.3 Recommendations for Future Work
Further investigation into the cyclization of the Ugi product must be performed. Isolation and characterization of the BOC de-protected intermediate could provide more information on transamidation. Compiling a library of Ugi adducts synthesized along with their kinetics information should be performed while gaining collaborators to test for any biological activities with other diseases.
8.4 Reference List
Bradley, JC http://usefulchem.blogspot.com/2007/04/nci-usefulchem-link.html 2007
Hooker, B. http://3quarksdaily.blogs.com/3quarksdaily/2007/01/the_future_of_s.html 2007